Our central hypothesis is that estrogen (E) deficiency acts through various tissue-specific mechanisms to account for most of the bone loss in aging women and for a substantial part of it in aging men. Specific Aim 1 will define possible direct versus indirect effects of E on parathyroid hormone (PTH) secretion, leading to a better understanding of the pathogenesis of the secondary hyperparathryoidism of elderly women by assessing PTH secretory dynamics in elderly women in whom E status has been experimentally altered. Protocol 2 will determine id osteoprotegrin (OPG), a newly discovered potent inhibitor of bone resorption and its cognitive ligand, (OPGL), are major paracrine mediators of E action on bone by measuring their bone marrow plasma levels in women followed transmenopausally with and without E therapy. Specific Aim 2 will determine if impaired OPG or excessive OPGL secretion predisposes some, but not other E deficient women to develop osteoporosis by measuring marrow plasma levels in untreated osteoporotic and non-osteoporotic postmenopausal women (Protocol 3). Specific Aim 3 will define the comparative roles for E. testosterone (T), and PTH in regulation bone turnover in elderly men. Protocol 4 will test directly for a causal role for the age-related increase in serum PTH levels in men in mediating increases in bone resorption. Protocol 5 will compare thje effects of E, T + E in preventing increased bone resorption induced by acute induction of hypogonadism with GnRH agonist administration in elderly men, and Protocol 6 will assess the effects of 6 month treatment of elderly men with placebo or raloxifene (which has an E agonist effect on bone but is not feminizing) on biochemical markers of bone turnover. These state-of-the-art studies will elucidate the role of E deficiency on the pathophysiology of bone loss and osteoporosis in postmenopausal and aging women and its contribution to bone loss in aging men and may lead to innovative types of therapy.